【科技前瞻】Nature：重磅！研究人员鉴定出新型干细胞可再生受损肠道

生物_医药_科研 2019-06-04

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肠道上皮的更替由位于隐窝区底部的多能性LGR5⁺隐窝基底柱状细胞（crypt-base columnar cell，CBC）驱动，CBC在受到辐射等刺激后会损伤并丢失，但是此时肠上皮仍然能够恢复。因此，有研究人员提出存在另一种静止的细胞，即储备干细胞（reserve stem cell，RSC）也能够再生受损的肠道。

此前，CBC和RSC被认为是相互排斥的，但近期研究发现LGR5⁺ CBC也表达RSC标志物，LGR5⁺细胞对于修复受损的肠道是必需的。此外，吸收性肠上皮细胞、分泌细胞和慢循环LGR5⁺细胞的祖细胞有助于促进再生，在肠道再生中起着重要作用的转录调节因子YAP1可以诱导LGR5⁺细胞产生促存活表型。但人们对细胞可塑性或不同的细胞群体对肠道再生的重要性仍然未知。近日，来自加拿大的研究人员利用单细胞RNA测序分析了小鼠肠道，鉴定出一种独特的可被损伤激活的静止细胞类型，被称为复活干细胞（revival stem cell，revSC）。相关研究结果发表在Nature期刊上。revSC以凝聚素高表达为特征，在稳态条件下非常少见，但可以产生所有主要的肠道细胞类型，包括LGR5⁺ CBC。在用辐射、靶向剔除LGR5⁺ CBC或右旋糖酐硫酸酯钠处理导致肠道受损后，revSC会进行YAP1依赖性的短暂增殖，重建LGR5⁺ CBC区室，最终再生功能性肠道。

该研究首次鉴定出了一类独特的干细胞，它们可因肠道损伤而被调动，进而恢复静态的干细胞区室，并且再生肠上皮。

推荐阅读原文：

Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell.

The turnover of the intestinal epithelium is driven by multipotent LGR5⁺ crypt-base columnar cells (CBCs) located at the bottom of crypt zones. However, CBCs are lost following injury, such as irradiation, but the intestinal epithelium is nevertheless able to recover. Thus, a second population of quiescent ‘+4’ cells, or reserve stem cells (RSCs), has previously been proposed to regenerate the damaged intestine. Although CBCs and RSCs were thought to be mutually exclusive, subsequent studies have found that LGR5⁺ CBCs express RSC markers and that RSCs were dispensable—whereas LGR5⁺ cells were essential—for repair of the damaged intestine. In addition, progenitors of absorptive enterocytes, secretory cells and slow cycling LGR5⁺ cells have been shown to contribute to regeneration whereas the transcriptional regulator YAP1, which is important for intestinal regeneration, was suggested to induce a pro-survival phenotype in LGR5⁺ cells. Thus, whether cellular plasticity or distinct cell populations are critical for intestinal regeneration remains unknown. Here we applied single-cell RNA sequencing to profile the regenerating mouse intestine and identified a distinct, damage-induced quiescent cell type that we term the revival stem cell (revSC). revSCs are marked by high clusterin expression and are extremely rare under homoeostatic conditions, yet give rise—in a temporal hierarchy—to all the major cell types of the intestine, including LGR5⁺ CBCs. After intestinal damage by irradiation, targeted ablation of LGR5⁺ CBCs, or treatment with dextran sodium sulfate, revSCs undergo a YAP1-dependent transient expansion, reconstitute the LGR5⁺ CBC compartment and are required to regenerate a functional intestine. These studies thus define a unique stem cell that is mobilized by damage to revive the homoeostatic stem cell compartment and regenerate the intestinal epithelium.